The role of KiSS1 gene on the tumor growth and migration of prostate cancer and the underlying molecular mechanisms

Background: Prostate cancers have a very high mortality rate, with no improvement in the survival rate being achieved over the past few decades. KiSS1 was originally identified as the metastasis suppressor gene in metastatic melanoma breast cancer, but its role in prostate cancer has been contradictory. This study was therefore undertaken to investigate the effects of KiSS1 overexpression on the growth and migration of human metastatic prostate cancer cells. Methods: DU145 human metastatic prostate cancer cells were infected with the culture medium of 293T cells, which produce lentivirus particles containing KiSS1 . The tumor spheroid formation assay, qPCR and immunoblotting analysis, migration and invasion assays were performed in this study following KiSS1 introduction. A xenograft mouse model was employed to investigate the overexpression of KiSS1 in prostate cancer in vivo . Results: A significant increase in proliferation of KiSS1 -overexpressing cancer cells was observed, and these cells formed tumor spheroids larger than the vector control group. qPCR and immunoblotting revealed the association between increased cell growth and regulation of the PI3K/Akt and cell cycle genes, and also that increases in β-catenin and CD133 contribute to tumor aggregation. KiSS1 overexpression resulted in upregulation of the β-arrestin1/2 and Raf-MEK-ERK-NF-κB pathways via KISS1R. Moreover, the migration and invasion of KiSS1 -overexpressing cells were determined to be faster than the control group, along with increased metastatic colonization of the KiSS1 -overexpressing cancer cells. These were associated to the regulation of EMT gene expressions, such as E-cadherin and N-cadherin, and the upregulation of MMP9. In the xenograft mouse model, KiSS1 significantly increased the tumor growth, with upregulation of PCNA and Ki-67 in the tumor tissues. In addition, KiSS1 increased the angiogenic capacity by upregulating VEGF-A and CD31, both in vitro and in vivo . Conclusion: These results indicate that KiSS1 not only induces prostate cancer proliferation, but also promotes metastasis by increasing the migration, invasion, and angiogenesis of malignant cells.